Keratinocyte growth factor is a mitogenic peptide growth factor involved in a broad range of cellular processes including hyperplasia, DNA synthesis, differentiation, cell cycle progression, and inhibition of apoptosis (Marchese et al., 1990, J. Cell Physiol. 144:326-32). These effects are mediated through binding to its tyrosine-kinase linked cell surface receptor, the KGF receptor.
Vitronectin is a glycoprotein that is highly abundant in the blood and in the extra cellular matrix (ECM). Primarily synthesized in the liver, but expressed by many other cell types, VN circulates in the blood in a closed conformation and is deposited in the ECM in an open, or extended, conformation (Schvartz et al., 1999, Int. J. Biochem. Cell Biol. 31:531-44). Both conformations are believed to bind IGF-II (Upton et al., 1999, Endocrinology 140:2928-31; International Publication WO 02/24219; McMurty et al., 1996, Endocrinology 150:149-60) and also bind multiple other ligands including collagen (Morris et al., 1994, J. Bio. Chem. 269:23845-52), glycosaminoglycans (Francois et al., 1999, J. Bio. Chem. 274:37611-19), many other ECM proteins, and a wide variety of integrins, particularly the αv integrins. Indeed, the primary role of vitronectin is as an ECM organization molecule that provides adhesive links to these cell surface integrin receptors via an RGD binding motif. The VN receptors (αv integrins) have been shown to regulate the actin cytoskeleton rearrangement required for growth and invasion, hence, VN binding coordinates cell adhesion and movement (DePasquale, 1998, Histochemistry and Cell Biology 110:485-94; Huang, 2000, Oncogene 19:1915-23).
However, the relative contributions of KGF and VN, and their respective domains, present in protein complexes, in terms of stimulating biological responses such as cell migration and/or proliferation, have remained elusive.